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Role of the Cholesterol Metabolite 27-Hydroxycholesterol in Breast and Prostate Cancer

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Role of the Cholesterol Metabolite 27-Hydroxycholesterol in Breast and Prostate Cancer University of North Dakota UND Scholarly Commons Theses and Dissertations Theses, Dissertations, and Senior Projects January 2016 Role Of The holesC terol Metabolite 27-Hydroxycholesterol In Breast And Prostate Cancer Shaneabbas S. Raza Follow this and additional works at: https://commons.und.edu/theses Recommended Citation Raza, Shaneabbas S., "Role Of The hoC lesterol Metabolite 27-Hydroxycholesterol In Breast And Prostate Cancer" (2016). Theses and Dissertations. 2067. https://commons.und.edu/theses/2067 This Dissertation is brought to you for free and open access by the Theses, Dissertations, and Senior Projects at UND Scholarly Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of UND Scholarly Commons. For more information, please contact [email protected]. ROLE OF THE CHOLESTEROL METABOLITE 27-HYDROXYCHOLESTEROL IN BREAST AND PROSTATE CANCER by Shaneabbas Shabbir Raza Bachelor of Arts, Minnesota State University Moorhead, 2012 A Dissertation Submitted to the Graduate Faculty of the University of North Dakota in partial fulfillment of the requirements for the degree of Doctor of Philosophy Grand Forks, North Dakota August 2016 Copyright 2016 Shaneabbas Raza ii PERMISSION Title Role of cholesterol metabolite, 27-hydroxycholesterol in breast and prostate cancer Department Pharmacology, Physiology and Therapeutics Degree Doctor of Philosophy In presenting this dissertation in partial fulfillment of the requirements for a graduate degree from the University of North Dakota, I agree that the library of this University shall make it freely available for inspection. I further agree that permission for extensive copying for scholarly purposes may be granted by the professor who supervised my dissertation work or, in his absence, by the Chairperson of the department or the dean of the School of Graduate Studies. It is understood that any copying or publication or other use of this thesis dissertation or part thereof for financial gain shall not be allowed without my written permission. It is also understood that due recognition shall be given to me and to the University of North Dakota in any scholarly use which may be made of any material in my dissertation. Shaneabbas Raza 07/10/2016 iv TABLE OF CONTENTS LIST OF FIGURES………………………………………………………………..…...vii LIST OF TABLES...………………………………………………………….…………ix ACKNOWLEDGEMENTS………………………………………………………………x GLOBAL ABSTRACT………………………………………………………….....……xii CHAPTER I. INTRODUCTION…………………………………………………..……1 Oxysterols: The Arcane Descendants of Cholesterol……….1 Breast Cancer……………………………………………………6 Prostate Cancer………………………………………………..11 II. ROLE OF 27-HYDROXYCHOLESTEROL IN BREAST CANCER…………………………………………………17 Abstract………...……………………………………………….17 Introduction……………………………………………………..18 Methods…………………………………………………………20 Results………………………………………………………….24 Discussion……………………………………………………...35 v III. ROLE OF 27-HYDROXYCHOLESTEROL IN PROSTATIC HYPERPLASIA……………………………………..42 Abstract………...……………………………………………….42 Introduction……………………………………………………..43 Methods…………………………………………………….…..45 Results………………………………………………………….50 Discussion……………………………………………………...61 IV. ROLE OF 27-HYDROXYCHOLESTEROL IN PROSTATE CANCER…..…………………………………………66 Abstract………...……………………………………………….66 Introduction……………………………………………………..67 Methods…………………………………………………………69 Results……..…………………………………………………...75 Discussion……………………………………………………...90 V. CONCLUDING REMARKS AND FUTURE DIRECTIONS……………………………………………….96 27-OHC and Breast Cancer…………………………………..96 27-OHC and Prostate Cancer………………………………..99 Future Directions……………………………………………..102 REFERENCES……………………………………………………………………….104 vi LIST OF FIGURES Figure Page 1. A diagram of the cholesterol biosynthetic pathway……………………….2 2. Structure of cholesterol and its main oxidation sites………………………4 3. A schematic diagram depicting the biosynthesis of the major oxysterols…………………………………………………………...5 4. A schematic diagram displaying the canonical progression of breast cancer pathology …………………………………………………………......7 5. A diagram depicting the classification of all breast cancers based on available immunohistochemistry marker profiles ………………………….9 6. A pictorial diagram depicting the difference and shared risks between BPH and PCa…………………………………………………………………13 7. Histopathology of Prostatic biopsy specimen……………………………..14 8. Stages of PCa and possible treatment regimens at various stages of the disease…………………………………………………………….…………..15 9. 27-OHC induces proliferation in breast cancer cell lines…………………25 10. 27-OHC reduces p53 activation…………………………………………….27 11. 27-OHC reduces p53 and increases MDM2 levels……………………….29 12. 27-OHC promotes p53-MDM2 interaction in MCF7 cells………………..31 13. 27-OHC induces proliferation via MDM2-mediated p53 inactivation…..34 14. Proposed mechanism of action of 27-OHC in ER+ breast cancer……..40 15. 27-OHC induces proliferation in prostate cells……………………………51 16. 27-OHC increases AR transcriptional activity…………………………….52 vii 17. 27-OHC increases PSA protein levels via AR……………………………54 18. 27-OHC-induced cell proliferation is AR dependent…………………….56 19. 27-OHC opposes docetaxel-induced apoptosis…………………………58 20. 27-OHC reduces docetaxel-induced caspase-3 cleavage……………..60 21. 27-OHC induces cell proliferation in PCa cells…………………………..77 22. 27-OHC stimulates cell proliferation via ER……………………………...79 23. 27-OHC upregulates ERβ expression…………………………………….81 24. 27-OHC induces cell proliferation via ERβ……………………………….83 25. 27-OHC reduces ECM invasion in PCa cells but not in non-tumorigenic cells…………………………………………………….85 26. 27-OHC differentially regulates ERβ2…………………………………….89 27. Schematic diagram of the role of 27-OHC in hormonal cancers……..101 viii LIST OF TABLES Table Page 1. Selected Genes analyzed with their corresponding pathways……………………………………………….…………………….73 2. Primers used in determining mRNA expression of significantly regulated genes……..……………………………………………………….74 3. Significantly regulated genes in absolute fold change…………………..87 ix ACKNOWLEDGEMENTS First off, I would like to thank my parents and siblings in Tanzania who not only made sacrifices for me but also inculcated in me the passion for knowledge and the determination to work hard. I owe a great deal of my success in graduate school to my mentor, Dr. Othman Ghribi. His influence on me goes well beyond his invaluable guidance, constant encouragement, constructive comments and immense motivation. I would like to thank him for not only the aforementioned deeds but also for inspiring me to be on the frontline of medicine. The lessons I learned from him transcend any amount of letters (titles) I earn, before and after my name. I would like to thank my committee members who not only were a great resource to me, but also abetted me in performing to my fullest potential. I would like to also thank my wife, Stephanie, for her unwavering support especially during difficult times in graduate school. x To my grandfather, the late Mohammed Hussein Raza My grandmother, the late Sughra Ali Nathoo My uncle, the late Vivian Almeida To my kids: “Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less” - Marie Curie (1867-1934) GLOBAL ABSTRACT The cholesterol metabolites known as oxysterols play an important role in maintaining cell homeostasis. They play vital roles in inflammation, cell growth, cell signaling, immunity, oxidative stress and aging. Following the discovery that the most abundant oxysterol, 27-hydroxycholesterol (27-OHC) is a Selective Estrogen Receptor Modulator (SERM), it has been implicated in hormonal cancers such as breast and uterine cancer. 27-OHC is a ligand of estrogen receptors (ER), a nuclear hormone receptor involved in cell growth and proliferation. The downstream events followed by 27-OHC-induced ER activation in the context of breast cancer is unknown. Also, the role of 27-OHC in prostate cancer is ill-defined given the involvement of ER in prostate cancer (PCa) and benign prostatic hyperplasia (BPH). Our studies delineate for the first time a potential cellular mechanism of action of 27-OHC in the context of ER+ breast cancer, whereby 27-OHC induced ER activation in ER+ MCF7 cells increases cell proliferation via perturbing the p53-MDM2 axis. We demonstrate that 27- OHC, through ER, exacerbated p53 inactivation via MDM2 resulting in an increase in cell proliferation in ER+ breast cancer cells. Next, we address the possibility of 27-OHC exacerbating prostate cancer cell proliferation. In the context of BPH and PCa, we show that 27-OHC not only increased cell proliferation in tumorigenic cell lines, LNCaP and PC3 but also in the non- tumorigenic cells, RWPE-1. We further demonstrate that 27-OHC- induced cell xii proliferation in prostate cells is specifically through ERβ. Given the tissue dependent selective ER modulation of 27-OHC, our novel findings suggest that 27-OHC activates ER signaling in the prostate. Altogether, our findings elucidate and establish the novel role and cellular mechanism of action of the oxysterol 27- OHC in the context of breast and prostate cancer. In the interest of discovering new therapeutic avenues for breast and prostate cancers, our work may aid in the development of novel therapies that could mitigate/halt/alleviate the progression of ER+ breast cancers and prostate cancers. xiii CHAPTER I INTRODUCTION Oxysterols: The Arcane Derivatives of Cholesterol Cholesterol is a critical component of the cell membranes of the cells. It helps to preserve the fluidity of the cell membranes which is vital to
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